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Asthma is a common airway disease associated with allergic inflammation. Environmental factors, such as pollens, pollution, insect-borne antigens, or commercial chemicals, cause this disease. The common symptoms of this airway allergic reaction are increasing mucus, narrowing of the airway wall, coughing, and chest tightness. Medications, such as steroids, alleviate the disease but with severe side effects. Several studies have reported the anti-inflammatory effects of tree-based essential oil components, particularly 3-carene. Therefore, this study used 3-carene to determine if it alleviates asthmatic symptoms in the murine model. First, BALB/c mice were sensitized to an ovalbumin and aluminum hydroxide mixture on day 7th and 14th. From days 21st to 23rd, the mice were challenged with 3-carene and budesonide. The lung trachea, plasma, and bronchiolar lavage fluid (BAL fluid) were collected on day 24. The 3-carene treatment suppressed the cytokine gene expression, such as interleukin-4 (IL-4), IL-5, and IL-13, reducing the lung epithelial cell thickness in the asthmatic model. These results suggest that essential oil 3-carene has an anti-asthmatic effect. [ABSTRACT FROM AUTHOR]

Silicosis is a refractory pneumoconiosis of unknown etiology that is characterized by diffuse lung fibrosis, and microRNA (miRNA) dysregulation is connected to silicosis. Emerging evidence suggests that miRNAs modulate pulmonary fibrosis through autophagy; however, its underlying molecular mechanism remains unclear. In agreement with miRNA microarray analysis, the qRT-PCR results showed that miR-29a-3p was significantly decreased in the pulmonary fibrosis model both in vitro and in vivo. Increased autophagosome was observed via transmission electron microscopy in lung epithelial cell models and lung tissue of silicosis mice. The expression of autophagy-related proteins LC3α/β and Beclin1 were upregulated. The results from using 3-methyladenine, an autophagy inhibitor, or rapamycin, an autophagy inducer, together with TGF-β1, indicated that autophagy attenuates fibrosis by protecting lung epithelial cells. In TGF-β1-treated TC-1 cells, transfection with miR-29a-3p mimics activated protective autophagy and reduced alpha-smooth muscle actin and collagen I expression. miRNA TargetScan predicted, and dual-luciferase reporter experiments identified Akt3 as a direct target of miR-29a-3p. Furthermore, Akt3 expression was significantly elevated in the silicosis mouse model and TGF-β1-treated TC-1 cells. The mammalian target of rapamycin (mTOR) is a central regulator of the autophagy process. Silencing Akt3 inhibited the transduction of the mTOR signaling pathway and activated autophagy in TGF-β1-treated TC-1 cells. These results show that miR-29a-3p overexpression can partially reverse the fibrotic effects by activating autophagy of the pulmonary epithelial cells regulated by the Akt3/mTOR pathway. Therefore, targeting miR-29a-3p may provide a new therapeutic strategy for silica-induced pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Background: The fundamental initial step in the metabolic process of fatty acids (FA) is facilitated by Acyl‐coenzyme A synthetase (ACS). ACS enables FAs to engage in both anabolic and catabolic pathways by creating thioester bonds with CoA, thus triggering their activation. This paper demonstrated the effect of in vitro cells on the ACS family of key enzymes in FA metabolism in response to inflammatory or lipid stimulating factors and provided insight into the relevant metabolic mechanisms. Methods: The expression levels of 27 ACS family members were assessed across various lung epithelial cell lines, such as HBE, SPC‐1A, or NCI‐H460, in response to external challenges including lipopolysaccharide (LPS), lysophosphatidylcholine (lysoPC), cigarette smoking extract (CSE), cholesterol, and interference with the ACSL5 gene in response to FASN, CPT1A inhibitors. Results: Our data showed that ACSF2 was highly expressed in SPC‐A1 and NCI‐H460 cells compared with HBE cell, while ACSL4 and ACSVL4 were lower expressed. The 27 ACS family genes associated with FA metabolism varied under several different exogenous stimuli. [ABSTRACT FROM AUTHOR]

Today, human organoids are becoming an integrated part of genomics and epigenomics, as they provide a platform that can be used for the definite study of molecular and cellular mechanisms occurring at different stages of development, particularly organogenesis, within the human body. Airway development is a complex process heavily influenced by epigenetic regulatory mechanisms in response to environmental changes, and as such, human lung organoids are an indispensable asset for further exploration of these mechanisms as a mode of transition from human in vitro to human ex vivo studies. Cultured primarily in compounds mimicking the extracellular matrix, such as Matrigel, these lung organoids have helped us to come to a better understanding of the role of polycomb repressive complex 2 (PRC2) and enhancer of zeste homolog 2 (EZH2) in lung epithelial cell differentiation and airway development, which was first reported in the FASEB journal in 2019. The following is an extended account of how the histone methylation‐regulating PRC2 comes to play in the molding of the human bronchial tree, along with further epigenetic insights based on more recently developed human lung organoids. [ABSTRACT FROM AUTHOR]

Abstract Background The fundamental initial step in the metabolic process of fatty acids (FA) is facilitated by Acyl‐coenzyme A synthetase (ACS). ACS enables FAs to engage in both anabolic and catabolic pathways by creating thioester bonds with CoA, thus triggering their activation. This paper demonstrated the effect of in vitro cells on the ACS family of key enzymes in FA metabolism in response to inflammatory or lipid stimulating factors and provided insight into the relevant metabolic mechanisms. Methods The expression levels of 27 ACS family members were assessed across various lung epithelial cell lines, such as HBE, SPC‐1A, or NCI‐H460, in response to external challenges including lipopolysaccharide (LPS), lysophosphatidylcholine (lysoPC), cigarette smoking extract (CSE), cholesterol, and interference with the ACSL5 gene in response to FASN, CPT1A inhibitors. Results Our data showed that ACSF2 was highly expressed in SPC‐A1 and NCI‐H460 cells compared with HBE cell, while ACSL4 and ACSVL4 were lower expressed. The 27 ACS family genes associated with FA metabolism varied under several different exogenous stimuli.

Fine particulate matter (PM2.5) has attracted more and more attention in the field of environmental pollution and public health. Previous studies have found that PM2.5 can be inhaled and deposit in the airway and alveoli, and even spread to the whole-body tissues and organs through blood, resulting in various toxic effects. The malignant transformation of lung epithelial cells associated with long-term exposure to PM2.5 may play an important role in the occurrence and development of lung cancer. This paper reviewed recent studies on the mechanisms of malignant transformation of lung epithelial cells associated with PM2.5 exposure, and discussed the main biological mechanisms, including epigenetics, tumor microenvironment, and other biological pathways. Besides, the potential research directions of malignant transformation of lung epithelial cells associated with PM2.5 exposure were proposed. This work aims to provide a scientific basis and reference for public health management and air quality assessment.

Background: Club cell secretory protein (CC16) has demonstrated utility as a lung-specific biomarker in predicting mortality in acute respiratory distress syndrome (ARDS). These findings have been observed in pre-clinical trials and a re-analysis of a large, randomized controlled trial of ARDS (Fluid and Catheter Treatment Trial (FACTT)). Objectives: The purpose of this study was to validate previous findings by evaluating CC16 level as a mortality predictor in patients from the albuterol to treat acute lung injury (ALTA) trial. Design and Method: In this secondary biomarker analysis, plasma CC16 level was measured from 100 ALTA subjects using enzyme-linked immunosorbent assay (ELISA). The rate of mortality was assessed in patients with high (⩾45 ng/mL) versus low CC16 (<45 ng/mL) levels. This cut-off level was applied based on our previous analysis from FACTT trial. Significance was assessed using Kaplan-Meier curves and a log-rank test. Results: Subjects were an average of 50 years old and 46% of them were females. Patients with high CC16 levels had higher 90-day mortality compared to those with low CC16 levels, (37.73% vs 8.95%, P <.001). Other clinical outcomes including ICU-free days, ventilator-free days, and organ failure free days were significantly different between the groups (All P <.05). Conclusion: In this validation study, we demonstrated that ARDS patients with high plasma CC16 concentration had a higher mortality rate than those with low CC16 levels, confirming previous findings that CC16 levels are associated with ARDS mortality. [ABSTRACT FROM AUTHOR]

Background and objective: Oxidative stress is a process that occurs through free radicals on the cell membranes which causes damage to the cell and intracellular organelles, especially mitochondria membranes. H2O2 induced oxidative stress in human cells is of interest in toxicological research since oxidative stress plays a main role in the etiology of several pathological conditions. Neutrophil Elastase (Serine proteinase) is involved in the pathology process of emphysema as a respiratory disease through lung inflammation, and destruction of alveolar walls. The present study investigated the direct oxidative stress effects of Elastase in comparison with H2O2 on human lung epithelial cells (A549 cells) concerning the generation of reactive oxygen species (ROS) and modulation of oxidation resistance 1 (OXR1) and its downstream pathway using the well-known antioxidant Ellagic acid as an activator of antioxidant genes. Materials and methods: The human pulmonary epithelial cells (A549) were divided into the nine groups including Negative control, Positive control (H2O2), Elastase (15, 30, and 60 mU/mL), Ellagic acid (10 μmol/L), and Elastase + Ellagic acid. Cytotoxicity, ROS generation, oxidative stress profile, level of reactive metabolites, and gene expression of OXR1 and its downstream genes were measured in all groups. Results: The obtained data demonstrated that Elastase exposure caused oxidative stress damage in a dose-depended manner which was associated with decreases in antioxidant defense system genes. Conversely, treatment with Ellagic acid as a potent antioxidant showed improved antioxidant enzyme activity and content which was in line with the upregulation of OXR1 signaling pathway genes. Conclusions: The present findings can highlight the novel mechanism underlying the oxidative stress induced by Neutrophil Elastase through OXR1 and related genes. Moreover, the benefit of Ellagic acid on cytoprotection, resulting from its antioxidant properties was documented. [ABSTRACT FROM AUTHOR]

Silicosis is a refractory pneumoconiosis of unknown etiology that is characterized by diffuse lung fibrosis, and microRNA (miRNA) dysregulation is connected to silicosis. Emerging evidence suggests that miRNAs modulate pulmonary fibrosis through autophagy; however, its underlying molecular mechanism remains unclear. In agreement with miRNA microarray analysis, the qRT-PCR results showed that miR-29a-3p was significantly decreased in the pulmonary fibrosis model both in vitro and in vivo. Increased autophagosome was observed via transmission electron microscopy in lung epithelial cell models and lung tissue of silicosis mice. The expression of autophagy-related proteins LC3α/β and Beclin1 were upregulated. The results from using 3-methyladenine, an autophagy inhibitor, or rapamycin, an autophagy inducer, together with TGF-β1, indicated that autophagy attenuates fibrosis by protecting lung epithelial cells. In TGF-β1-treated TC-1 cells, transfection with miR-29a-3p mimics activated protective autophagy and reduced alpha-smooth muscle actin and collagen I expression. miRNA TargetScan predicted, and dual-luciferase reporter experiments identified Akt3 as a direct target of miR-29a-3p. Furthermore, Akt3 expression was significantly elevated in the silicosis mouse model and TGF-β1-treated TC-1 cells. The mammalian target of rapamycin (mTOR) is a central regulator of the autophagy process. Silencing Akt3 inhibited the transduction of the mTOR signaling pathway and activated autophagy in TGF-β1-treated TC-1 cells. These results show that miR-29a-3p overexpression can partially reverse the fibrotic effects by activating autophagy of the pulmonary epithelial cells regulated by the Akt3/mTOR pathway. Therefore, targeting miR-29a-3p may provide a new therapeutic strategy for silica-induced pulmonary fibrosis.

Conventional drug screening methods search for a limited number of small molecules that directly interact with the target protein. This process can be slow, cumbersome and has driven the need for developing new drug screening approaches to counter rapidly emerging diseases such as COVID-19. We propose a pipeline for drug repurposing combining in silico drug candidate identification followed by in vitro characterization of these candidates. We first identified a gene target of interest, the entry receptor for the SARS-CoV-2 virus, angiotensin converting enzyme 2 (ACE2). Next, we employed a gene expression profile database, L1000-based Connectivity Map to query gene expression patterns in lung epithelial cells, which act as the primary site of SARS-CoV-2 infection. Using gene expression profiles from 5 different lung epithelial cell lines, we computationally identified 17 small molecules that were predicted to decrease ACE2 expression. We further performed a streamlined validation in the normal human epithelial cell line BEAS-2B to demonstrate that these compounds can indeed decrease ACE2 surface expression and to profile cell health and viability upon drug treatment. This proposed pipeline combining in silico drug compound identification and in vitro expression and viability characterization in relevant cell types can aid in the repurposing of FDA-approved drugs to combat rapidly emerging diseases.

Background: Innate immune responses to influenza A virus (IAV) infection are initiated in part by toll-like receptor 3 (TLR3). TLR3-dependent signaling induces an antiviral immune response and an NFκB-dependent inflammatory response. Protease-activated receptor 2 (PAR2) inhibits the antiviral response and enhances the inflammatory response. PAR2 deficiency protected mice during IAV infection. However, the PAR2 expressing cell-types contributing to IAV pathology in mice and the mechanism by which PAR2 contributes to IAV infection is unknown. Methods: IAV infection was analyzed in global (Par2-/-), myeloid (Par2 fl/fl;LysMCre+) and lung epithelial cell (EpC) Par2 deficient (Par2fl/fl ;SPCCre+) mice and their respective controls (Par2 +/+ and Par2 fl/fl). In addition, the effect of PAR2 activation on polyinosinic-polycytidylic acid (poly I:C) activation of TLR3 was analyzed in bone marrow-derived macrophages (BMDM). Lastly, we determined the effect of PAR2 inhibition in wild-type (WT) mice. Results: After IAV infection, Par2-/- and mice with myeloid Par2 deficiency exhibited increased survival compared to infected controls. The improved survival was associated with reduced proinflammatory mediators and reduced cellular infiltration in bronchoalveolar lavage fluid (BALF) of Par2-/- and Par2 fl/fl;LysMCre+ 3 days post infection (dpi) compared to infected control mice. Interestingly, Par2 fl/fl;SPCCre+ mice showed no survival benefit compared to Par2fl/fl. In vitro studies showed that Par2-/- BMDM produced less IL6 and IL12p40 than Par2 +/+ BMDM after poly I:C stimulation. In addition, activation of PAR2 on Par2 +/+ BMDM increased poly I:C induction of IL6 and IL12p40 compared to poly I:C stimulation alone. Importantly, PAR2 inhibition prior to IAV infection protect WT mice. Conclusion: Global Par2 or myeloid cell but not lung EpC Par2 deficiency was associated with reduced BALF inflammatory markers and reduced IAV-induced mortality. Our study suggests that PAR2 may be a therapeutic target to reduce IAV pathology. [ABSTRACT FROM AUTHOR]

BackgroundInnate immune responses to influenza A virus (IAV) infection are initiated in part by toll-like receptor 3 (TLR3). TLR3-dependent signaling induces an antiviral immune response and an NFκB-dependent inflammatory response. Protease-activated receptor 2 (PAR2) inhibits the antiviral response and enhances the inflammatory response. PAR2 deficiency protected mice during IAV infection. However, the PAR2 expressing cell-types contributing to IAV pathology in mice and the mechanism by which PAR2 contributes to IAV infection is unknown.MethodsIAV infection was analyzed in global (Par2-/-), myeloid (Par2fl/fl;LysMCre+) and lung epithelial cell (EpC) Par2 deficient (Par2fl/fl;SPCCre+) mice and their respective controls (Par2+/+ and Par2fl/fl). In addition, the effect of PAR2 activation on polyinosinic-polycytidylic acid (poly I:C) activation of TLR3 was analyzed in bone marrow-derived macrophages (BMDM). Lastly, we determined the effect of PAR2 inhibition in wild-type (WT) mice.ResultsAfter IAV infection, Par2-/- and mice with myeloid Par2 deficiency exhibited increased survival compared to infected controls. The improved survival was associated with reduced proinflammatory mediators and reduced cellular infiltration in bronchoalveolar lavage fluid (BALF) of Par2-/- and Par2fl/fl;LysMCre+ 3 days post infection (dpi) compared to infected control mice. Interestingly, Par2fl/fl;SPCCre+ mice showed no survival benefit compared to Par2fl/fl. In vitro studies showed that Par2-/- BMDM produced less IL6 and IL12p40 than Par2+/+ BMDM after poly I:C stimulation. In addition, activation of PAR2 on Par2+/+ BMDM increased poly I:C induction of IL6 and IL12p40 compared to poly I:C stimulation alone. Importantly, PAR2 inhibition prior to IAV infection protect WT mice.ConclusionGlobal Par2 or myeloid cell but not lung EpC Par2 deficiency was associated with reduced BALF inflammatory markers and reduced IAV-induced mortality. Our study suggests that PAR2 may be a therapeutic target to reduce IAV pathology.

Aim: This work aims to standardize the three-dimensional hydroxyethyl-alginate-gelatin (HAG) scaffold as a model to evaluate Aspergillus fumigatus biofilm and antifungal treatments. Methods: The scaffold was characterized by physical, rheological and microscopic analyses; the antibiofilm action was evaluated by determination of cfu and metabolic activity. Results: The scaffold was non-toxic showing stability in aqueous media, swelling capacity, elasticity and had homogeneously distributed pores averaging 190 μm. The A. fumigatus biofilm established itself very well on the scaffold and treatment with amphotericin B and voriconazole reduced viable cells and metabolic activity. Conclusion: The HAG scaffold proved to be a model to mimic lung parenchyma, suitable for establishing a 3D biofilm culture of A. fumigatus and evaluating the efficacy of antifungals.

Objective Based on the high-throughput sequencing data of the whole genome， genomics and bioinformatics analyses were made to analyze the gene expression changes in the epithelial cells of the lung tissue from patients with coronavirus disease 2019 （COVID-19）， and explore the effects of the new coronavirus SARS-CoV-2 on human lungs. This study can provide a theoretical basis for the exploration of SARS-CoV-2 on the pathogenesis of lung tissue. Methods The public data set GSE160435 was retrieved. The data were analyzed by Network analyst， Cytoscape 3.7.2， String 11.0， and other software. The differentially expressed genes were screened， gene function （Gene Ontology， GO） and signal pathway KEGG （Kyoto Encyclopedia of Genes and Genomes） enrichment analysis were carried out. We established the Protein-protein Interactions Network （PPI）， PPI of lung tissue-specific DEGs， DEG microRNA regulatory network， Transcription Factor （TF）-DEG regulatory network， and environmental chemicals DEGs regulatory network. Results We found 324 DEGs in the lung epithelial cells of patients with COVID-19， of which 112 （34.57%） were upregulated and 212 （65.43%） were downregulated. Enrichment analysis showed that DEGs were mainly involved in biological processes such as virus-related defense response， mainly involved in protein digestion and absorption， anti-human papillomavirus infection and other signaling pathways. Specific PPI network closely related to DEGs and lung tissue showed that PDGFRB and KIT were core proteins； hsa-mir-340 had targeted interaction with DEGs. It indicated that HOXB4， ISG15 and other related genes were regulated by transcription factors； DEGs interacted with environmental chemicals such as nickel and estradiol. Conclusion The gene expression pattern of lung epithelial cells in lung tissue of COVID-19 patients has changed significantly. Proteins or genes such as PDGFRB， MMP9 and KIT may play a vital role in the defense immunity of lung tissue. Micro-RNA， TF， signaling pathway molecules， environmental chemicals， and lung tissue-specific genes also play a role in the above-mentioned process. This study provides new ideas for exploring the pathogenic mechanism of SARS-CoV-2 on lung tissue and formulating clinical prevention， diagnosis and treatment measures. [ABSTRACT FROM AUTHOR]

Mycoplasma pneumoniae-induced pneumonia (MPP) is a common cause of community-acquired respiratory tract infections, increasing risk of morbidity and mortality, in children. However, diagnosing early-stage MPP is difficult owing to the lack of good diagnostic methods. Here, we examined the protein profile of bronchoalveolar lavage fluid (BALF) and found that S100A8/A9 was highly expressed. Enzyme-linked immunosorbent assays used to assess protein levels in serum samples indicated that S100A8/A9 concentrations were also increased in serum obtained from children with MPP, with no change in S100A8/A9 levels in children with viral or bacterial pneumonia. In vitro, S100A8/A9 treatment significantly increased apoptosis in a human alveolar basal epithelial cell line (A549 cells). Bioinformatics analyses indicated that up-regulated S100A8/A9 proteins participated in the interleukin (IL)−17 signaling pathway. The origin of the increased S100A8/A9 was investigated in A549 cells and in neutrophils obtained from children with MPP. Treatment of neutrophils, but not of A549 cells, with IL-17A released S100A8/A9 into the culture medium. In summary, we demonstrated that S100A8/A9, possibly released from neutrophils, is a new potential biomarker for the clinical diagnosis of children MPP and involved in the development of this disease through enhancing apoptosis of alveolar basal epithelial cells.

Abstract Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis, resulting in poor patient prognosis. An aberrant recapitulation of developmental lung gene expression, including genes for transforming growth factor (TGF)‐β and WNT, has been widely implicated in the pathogenic IPF wound healing process that results from repetitive alveolar epithelial injury. Extracellular vesicles (EVs) have been shown to carry bioactive molecules and to be involved in various physiological and pathological processes. Here, we demonstrate that, by attenuating WNT signalling, human bronchial epithelial cell‐derived EVs (HBEC EVs) inhibit TGF‐β mediated induction of both myofibroblast differentiation and lung epithelial cellular senescence. This effect of HBEC EVs is more pronounced than that observed with mesenchymal stem cell‐derived EVs. Mechanistically, the HBEC EV microRNA (miRNA) cargo is primarily responsible for attenuating both myofibroblast differentiation and cellular senescence. This attenuation occurs via inhibition of canonical and non‐canonical WNT signalling pathways. Among enriched miRNA species present in HBEC EVs, miR‐16, miR‐26a, miR‐26b, miR‐141, miR‐148a, and miR‐200a are mechanistically involved in reducing WNT5A and WNT10B expression in LFs, and in reducing WNT3A, WNT5A, and WNT10B expression in HBECs. Mouse models utilizing intratracheal administration of EVs demonstrate efficient attenuation of bleomycin‐induced lung fibrosis development accompanied by reduced expression of both β‐catenin and markers of cellular senescence. These findings indicate that EVs derived from normal resident lung HBECs may possess anti‐fibrotic properties. They further suggest that, via miRNA‐mediated inhibition of TGF‐β‐WNT crosstalk, HBEC EVs administration can be a promising anti‐fibrotic modality of treatment for IPF.

Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis, resulting in poor patient prognosis. An aberrant recapitulation of developmental lung gene expression, including genes for transforming growth factor (TGF)‐β and WNT, has been widely implicated in the pathogenic IPF wound healing process that results from repetitive alveolar epithelial injury. Extracellular vesicles (EVs) have been shown to carry bioactive molecules and to be involved in various physiological and pathological processes. Here, we demonstrate that, by attenuating WNT signalling, human bronchial epithelial cell‐derived EVs (HBEC EVs) inhibit TGF‐β mediated induction of both myofibroblast differentiation and lung epithelial cellular senescence. This effect of HBEC EVs is more pronounced than that observed with mesenchymal stem cell‐derived EVs. Mechanistically, the HBEC EV microRNA (miRNA) cargo is primarily responsible for attenuating both myofibroblast differentiation and cellular senescence. This attenuation occurs via inhibition of canonical and non‐canonical WNT signalling pathways. Among enriched miRNA species present in HBEC EVs, miR‐16, miR‐26a, miR‐26b, miR‐141, miR‐148a, and miR‐200a are mechanistically involved in reducing WNT5A and WNT10B expression in LFs, and in reducing WNT3A, WNT5A, and WNT10B expression in HBECs. Mouse models utilizing intratracheal administration of EVs demonstrate efficient attenuation of bleomycin‐induced lung fibrosis development accompanied by reduced expression of both β‐catenin and markers of cellular senescence. These findings indicate that EVs derived from normal resident lung HBECs may possess anti‐fibrotic properties. They further suggest that, via miRNA‐mediated inhibition of TGF‐β‐WNT crosstalk, HBEC EVs administration can be a promising anti‐fibrotic modality of treatment for IPF. [ABSTRACT FROM AUTHOR]

Toll-like receptor (TLR) 4 was originally thought to be the sole pattern recognition receptor for lipopolysaccharide (LPS). Transient receptor potential ankyrin 1 (TRPA1), a Ca2+-permeant channel, has been suggested as a non-TLR receptor membrane-bound sensor of LPS. We recently reported that TRPA1 is expressed in lung epithelial cells (LECs) and mediates lung inflammation induced by cigarette smoke. However, the role of TRPA1 in LPS-induced lung inflammation has not been conclusively defined, and its underlying cellular mechanisms remain unclear. In this study, our in vitro results showed that LPS sequentially produced a cascade of events, including the elevation of intracellular Ca2+, the activation of NADPH oxidase, increase in intracellular reactive oxygen species (ROS), the activation of mitogen-activated protein kinase (MAPK)/nuclear factor-kB (NF-κB) signaling, and the induction of IL-8. The increase in intracellular Ca2+ was inhibited by HC030031 (a TRPA1 antagonist) but was unaffected by TAK-242 (a TLR-4 inhibitor). The activation of NADPH oxidase was prevented by its inhibitor apocynin, EGTA (an extracellular Ca2+ chelator), and HC030031. The increase in intracellular ROS was attenuated by apocynin, N-acetyl-cysteine (NAC, a ROS scavenger), EGTA, and HC030031. The activation of the MAPK/NF-κB signaling was halted by NAC, EGTA, and HC030031. IL-8 induction was suppressed by HC030031 and TRPA1 siRNA, and further reduced by the combination of HC030031 and TAK-242. Our in vivo studies showed that trpa1–/– mice exhibited a reduced level of LPS-induced lung inflammation compared with wild-type mice as evidenced by the alleviations of increases in vascular permeability, inflammatory cell infiltration, inflammatory cytokine levels, oxidative stress, and MAPK signaling activation. Thus, in LECs, LPS may activate TRPA1 resulting in an increase in Ca2+ influx. The increased intracellular Ca2+ leads to NADPH oxidase activation, which causes an increase in intracellular ROS. The intracellular ROS activates the MAPK/NF-κB signaling resulting in IL-8 induction. This mechanism may possibly be at work to induce lung inflammation in mice.

Toll-like receptor (TLR) 4 was originally thought to be the sole pattern recognition receptor for lipopolysaccharide (LPS). Transient receptor potential ankyrin 1 (TRPA1), a Ca2+-permeant channel, has been suggested as a non-TLR receptor membrane-bound sensor of LPS. We recently reported that TRPA1 is expressed in lung epithelial cells (LECs) and mediates lung inflammation induced by cigarette smoke. However, the role of TRPA1 in LPS-induced lung inflammation has not been conclusively defined, and its underlying cellular mechanisms remain unclear. In this study, our in vitro results showed that LPS sequentially produced a cascade of events, including the elevation of intracellular Ca2+, the activation of NADPH oxidase, increase in intracellular reactive oxygen species (ROS), the activation of mitogen-activated protein kinase (MAPK)/nuclear factor-kB (NF-κB) signaling, and the induction of IL-8. The increase in intracellular Ca2+ was inhibited by HC030031 (a TRPA1 antagonist) but was unaffected by TAK-242 (a TLR-4 inhibitor). The activation of NADPH oxidase was prevented by its inhibitor apocynin, EGTA (an extracellular Ca2+ chelator), and HC030031. The increase in intracellular ROS was attenuated by apocynin, N-acetyl-cysteine (NAC, a ROS scavenger), EGTA, and HC030031. The activation of the MAPK/NF-κB signaling was halted by NAC, EGTA, and HC030031. IL-8 induction was suppressed by HC030031 and TRPA1 siRNA, and further reduced by the combination of HC030031 and TAK-242. Our in vivo studies showed that trpa1–/– mice exhibited a reduced level of LPS-induced lung inflammation compared with wild-type mice as evidenced by the alleviations of increases in vascular permeability, inflammatory cell infiltration, inflammatory cytokine levels, oxidative stress, and MAPK signaling activation. Thus, in LECs, LPS may activate TRPA1 resulting in an increase in Ca2+ influx. The increased intracellular Ca2+ leads to NADPH oxidase activation, which causes an increase in intracellular ROS. The intracellular ROS activates the MAPK/NF-κB signaling resulting in IL-8 induction. This mechanism may possibly be at work to induce lung inflammation in mice. [ABSTRACT FROM AUTHOR]

The mTOR pathway is one of the key signal cascades in the pathogenesis of idiopathic pulmonary fibrosis. Previous studies have mainly focused on this pathway in the fibroblasts and/or myofibroblasts, but not in the epithelial cells. In this study, we sought to investigate the role of the mTOR pathway in lung epithelial cells in lung fibrosis. Using Sftpc-mTORSL+IT transgenic mice, in which activemTORis conditionally expressed in lung epithelial cells, we assessed the effects of chronically activated mTOR in lung epithelial cells on lung phenotypes as well as bleomycin-induced lung fibrosis. Furthermore, we isolated alveolar epithelial cell type 2 frommice and performed RNA sequencing. Sftpc-mTORSL11IT transgenic mice had no obvious abnormal findings, but, after bleomycin administration, showed more severe fibrotic changes and lower lung compliance than control mice. RNA sequencing revealed Angptl4 (angiopoietin-like protein 4) as a candidate downstream gene of the mTOR pathway. In vitro studies revealed that ANGPTL4, as well as mTOR, promoted tight junction vulnerability and epithelial-mesenchymal transition. mTOR activation in lung epithelial cells promoted lung fibrosis and the expression of ANGPTL4, a novel downstream target of the mTOR pathway, which could be related to the etiology of fibrosis. [ABSTRACT FROM AUTHOR]

To investigate whether exposure to particulate matter of diameter equal to or less than 2.5 μm (PM 2.5) alters the response of lung epithelial cells to extrinsic regulation by globally profiling cell surface ligands and quantifying their binding activity. Human A549 lung epithelial cells (LECs) were treated with or without PM 2.5. Ligandomic profiling was applied to these cells for the global identification of LEC-binding ligands with simultaneous quantification of binding activity. Quantitative comparisons of the entire ligandome profiles systematically identified ligands with increased or decreased binding to PM 2.5 -treated LECs. We found 143 ligands with increased binding to PM 2.5 -treated LECs and 404 ligands with decreased binding. Many other ligands showed no change in binding activity. For example, apolipoprotein E (ApoE), Notch2, and growth arrest-specific 6 (Gas6) represent ligands with increased, decreased, or unchanged binding activity, respectively. Both ApoE and Gas6 are phagocytosis ligands, suggesting that phagocytic receptors on LECs after stimulation with PM 2.5 were differentially upregulated by PM 2.5. These results suggest that the newly-developed ligandomics is a valuable approach to globally profile the response of LECs to PM 2.5 in terms of regulating the expression of cell surface receptors, as quantified by ligand binding activity. This quantitative ligandome profiling will provide indepth understanding of the LEC molecular response on the cell surface to particulate matter air pollution. [ABSTRACT FROM AUTHOR]

Cigarette smoke (CS) contains many free radicals and toxic chemicals. Nuclear erythroid-related factor-2 (Nrf2) is a transcriptional regulator of several phase II antioxidant genes, including glutamate-cysteine ligase (GCL). In this study, it was hypothesized that Crocin may mediate antioxidant signaling pathway to protect human lung epithelial cells against CS-mediated toxicity and oxidative stress via inducing glutathione (GSH) biosynthesis and activation of Nrf2 pathway. Alveolar epithelial cells (A549) were exposed to 1, 2.5 and 5% cigarette smoke extracts (CSE) with or without Crocin (500 μM). After 48 h exposure, the cytotoxicity, oxidant/antioxidant parameters and the Nrf2 pathway modification were assayed. Treatment of A549 cells with all concentrations of CSE dose dependently decreased cell viability, antioxidant levels, GCL and Nrf2 gene expression, which was associated with increased production of reactive oxygen species. Crocin not only restored CSE-depleted GSH levels by enhancing GCL expression via activation of Nrf2 but also quenched the CSE-generation and release of reactive oxygen species. Crocin attenuated CSE-mediated Nrf2 modifications, thereby inducing its nuclear accumulation associated with GCL gene transcription leading to enhanced GSH levels. By inducing GSH synthesis, Crocin attenuates CSE-mediated GSH depletion and protects cells against CSE-induced oxidative stress via Nrf2 pathway. These results may have implications in dietary modulation of natural antioxidants in treatment of pulmonary diseases. [ABSTRACT FROM AUTHOR]

Cigarette smoking increases susceptibility for microbial infection in respiratory system. However, the underlying molecular mechanism(s) is not fully elucidated. Here we report that cigarette smoking extract (CSE) increases bacterial load in lung epithelial cells via downregulation of the ubiquitin-specific protease 25 (USP25)/histone deacetylase 11 (HDAC11) axis. CSE treatment decreases HDAC11 at protein level in lung epithelial cells without significant changes of its transcription. Concomitantly, CSE treatment accelerates a ubiquitin-specific protease USP25 ubiquitination and degradation. Coimmunoprecipitation studies showed that USP25 associated with HDAC11. USP25 catalyzes deubiquitination of HDAC11, which regulates HDAC11 protein stability. CSE-mediated degradation of USP25 thereafter reduces HDAC11 at the protein level. Interestingly, CSE-downregulated USP25/HDAC11 axis increases the bacterial load of Pseudomonas aeruginosa in lung epithelial cells. These findings suggest that CSE-downregulated USP25 and HDAC11 may contribute to high susceptibility of bacterial infection in the cigarette smoking population. [ABSTRACT FROM AUTHOR]

Purpose: The combined toxicity of alpha particles and cigarette smoke to the critical cells in the lungs was investigated to assess the risk of smoking workers who handle naturally occurring radioactive materials. Materials and methods: The toxicity of alpha particles and cigarette smoke extract (CSE) was evaluated in terms of DNA double-strand break (DSB) induction and clonogenic cell death of human lung epithelial cells in vitro. The cells were exposed to alpha particles at doses of up to 0.25 Gy for gamma-H2AX assay and from 1.25 Gy to 5 Gy for clonogenic assay. CSE exposure of the cells was facilitated in the culture medium at CSE concentrations ranging from 1% to 12%. Additional experiments were performed using mouse endothelial cells for comparison. Results: The increases in the levels of DNA DSBs were linearly dependent on radiation dose and CSE concentration. The CSE-treated cells also responded with a linearly increasing number of DNA DSBs to the radiation dose. Both human lung epithelial cells and mouse endothelial cells showed exponential decreases in clonogenic surviving fraction as the dose from alpha particle exposure increased. Both cells responded with the clonogenic surviving fractions decreasing in a linear proportion to the CSE concentration in the culture medium. Conclusion: In our experimental in vitro setup, CSE treatment and alpha particle exposure affected the cells in an additive manner either for DNA DSB production or for clonogenic cell death induction. [ABSTRACT FROM AUTHOR]

Abstract Inhalation of combustion-derived particles is associated with the development of age-related diseases like chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. In both diseases senescence of lung epithelial cells has been observed. Employing an in vitro system of repetitive exposure to pure carbon nanoparticles we asked whether this kind of particles are able to induce a senescent like phenotype, which might be accompanied by a loss of functionality at the level of gap junctional intercellular communication. Non-cytotoxic doses of carbon nanoparticles but not of bigger carbon particles led to an irreversible reduction of the proliferative capacity accompanied by the accumulation of the cell cycle blocking proteins p21 and p16 as well as a loss of both redox sensitive histone deacetylase SIRT1 and connexin-43. Gap junction intercellular communication detected by microinjection of fluorescent lucifer yellow was dramatically decreased after exposure. This loss of functionality was associated with a reduction of Connexin 43 at the plasma membrane. As the experimental system was chosen to study the effects of pure carbon nanoparticles in the absence of inflammatory cells, the data indicate that cumulative long-term exposure of the lung epithelium to low doses of combustion-derived nanoparticles might contribute to epithelial senescence and age-associated diseases of the airways. Highlights • Carbon nanoparticles and not carbon particles induce a senescent like phenotype in lung epithelial cells. • Carbon nanoparticles and not carbon particles induce loss of cell-cell communication • Carbon nanoparticles may induce dysfunctional lung epithelial cells [ABSTRACT FROM AUTHOR]

This paper reports a biomimetic microfluidic device capable of reconstituting physiological physical microenvironments in lungs during fetal development for cell culture. The device integrates controllability of both hydrostatic pressure and cyclic substrate deformation within a single chip to better mimic the in vivo microenvironments. For demonstration, the effects of drug treatment and physical stimulations on surfactant protein C (SPC) expression of lung epithelial cells (A549) are studied using the device. The experimental results confirm the device’s capability of mimicking in vivo microenvironments with multiple physical stimulations for cell culture applications. Furthermore, the results indicate the critical roles of physical stimulations in regulating cellular behaviors. With the demonstrated functionalities and performance, the device is expected to provide a powerful tool for further lung development studies that can be translated to clinical observation in a more straightforward manner. Consequently, the device is promising for construction of more in vitro physiological microenvironments integrating multiple physical stimulations to better study organ development and its functions.

Clinical studies suggest that smokers with chronic obstructive pulmonary disease who use menthol cigarettes may display more severe lung inflammation than those who smoke non-menthol cigarette. However, the mechanisms for this difference remain unclear. Menthol is a ligand of transient receptor potential melastatin-8 (TRPM8), a Ca2+-permeant channel sensitive to reactive oxygen species (ROS). We previously reported that exposure of human bronchial epithelial cells (HBECs) to non-menthol cigarette smoke extract (Non-M-CSE) triggers a cascade of inflammatory signaling leading to IL-8 induction. In this study, we used this in vitro model to compare the inflammatory effects of menthol cigarette smoke extract (M-CSE) and Non-M-CSE and delineate the mechanisms underlying the differences in their impacts. Compared with Non-M-CSE, M-CSE initially increased a similar level of extracellular ROS, suggesting the equivalent oxidant potency. However, M-CSE subsequently produced more remarkable elevations in intracellular Ca2+, activation of the mitogen-activated protein kinases (MAPKs)/nuclear factor-κB (NF-κB) signaling, and IL-8 induction. The extracellular ROS responses to both CSE types were totally inhibited by N-acetyl-cysteine (NAC; a ROS scavenger). The intracellular Ca2+ responses to both CSE types were also totally prevented by NAC, AMTB (a TRPM8 antagonist), or EGTA (an extracellular Ca2+ chelator). The activation of the MAPK/NF-κB signaling and induction of IL-8 to both CSE types were suppressed to similar levels by NAC, AMTB, or EGTA. These results suggest that, in addition to ROS generated by both CSE types, the menthol in M-CSE may act as another stimulus to further activate TRPM8 and induce the observed responses. We also found that menthol combined with Non-M-CSE induced greater responses of intracellular Ca2+ and IL-8 compared with Non-M-CSE alone. Moreover, we confirmed the essential role of TRPM8 in these responses to Non-M-CSE or M-CSE and the difference in these responses between the both CSE types using HBECs with TRPM8 knockdown and TRPM8 knockout, and using HEK293 cells transfected with hTRPM8. Thus, compared with exposure to Non-M-CSE, exposure to M-CSE induced greater TRPM8-mediated inflammatory responses in HBECs. These augmented effects may be due to a double-hit on lung epithelial TRPM8 by ROS generated from CSE and the menthol in M-CSE. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β2 (TGF-β2) plays an important role in pleiotropic functions and has been reported to be involved in the pathogenesis of chronic obstructive lung disease. The role of TGF-β2 in regulating cigarette smoke (CS)-induced lung inflammation and injury has not been investigated, and its underlying mechanism remains unclear. Primary bronchial epithelial cells (PBECs) were treated with cigarette smoke extract (CSE), and the signaling pathway of TGF-β2 regulating lung inflammation was investigated. Mice were exposed to CS and treated with TGF-β2 i.p. or bovine whey protein extract containing TGF-β2 p.o., and the role of TGF-β2 in alleviating lung inflammation/injury was studied. In vitro, we demonstrated that TGF-β2 attenuated CSE-induced IL-8 production from PBECs through the TGF-β receptor I (TGF-βRI), Smad3, and mitogen-activated protein kinase signaling pathways. Selective TGF-βRI inhibitor (LY364947) and antagonist of Smad3 (SIS3) abolished the effect of TGF-β2 on alleviating CSE-induced IL-8 production. In vivo, CS exposure for 4 weeks in mice increased the levels of total protein, inflammatory cell counts, and monocyte chemoattractant protein-1 in bronchoalveolar fluid and induced lung inflammation/injury, as revealed by immunohistochemistry. Administration of TGF-β2 through intraperitoneal injection or oral feeding with bovine whey protein extract containing TGF-β2 significantly reduced CS-induced lung inflammation and injury. We concluded that TGF-β2 reduced CSE-induced IL-8 production through the Smad3 signaling pathway in PBECs and alleviated lung inflammation/injury in CS-exposed mice. The anti-inflammatory effect of TGF-β2 on CS-induced lung inflammation in humans deserves further clinical study. [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON) is an important Fusarium toxin of concern for food safety. The inhalation of powder contaminated with DON is possible and may cause lung toxicity. In this study, we analyzed the gene expression profile of A549 cells treated for 24 hr with 0.2 µg/mL DON by microarray analysis. In total, 16 genes and 5 noncoding RNAs were significantly affected by DON treatment. The repression of B3GALT4, MEIS3, AK7, SEMA3A, KCNMB4, and SCARA5 was confirmed by quantitative PCR. We investigated the DON toxicity on A549 cells that exogenously expressed these 6 genes. The result indicated that A549 cells that transiently expressed MEIS3 were tolerant to the deleterious effects of DON. Our data show that DON affected the expression of genes with various functions, and suggest that the repression of MEIS3 plays roles in the deleterious effect of DON in A549 lung epithelial cells. [ABSTRACT FROM AUTHOR]

Background: Mitochondria mediate airway inflammatory responses to cigarette smoke (CS). Removal of damaged or defective mitochondrial (mitophagy) may prevent the detrimental impact of CS extract (CSE) on airway and lung epithelial cells., Methods: We studied the effect of a mitophagy activator (Urolithin A, UA) and a mitophagy inhibitor (Liensinine diperchlorate, Ld) on CSE-exposed alveolar (A549) and airway (BEAS-2B) epithelial cell proliferation, intracellular and mitochondrial ROS, inflammatory response, mitochondrial membrane potential (Δψm), mitochondrial morphology, mitochondrial complex activities, and protein levels of mitochondrial fission (DRP1, MFF) and mitophagy (SQSTM1/p62, LC3B). In both cell types, CSE exposure led to increased intracellular and mitochondrial oxidative stress, decreased Δψm and resulted in structural disruption of the mitochondrial network. CSE increased the expression of DRP1, MFF and SQSTM1/p62 while decreasing LC3B-II/I protein expression ratio. CSE also increased inflammatory (IL-1β, IL-6, IL-18, CXCL1, CXCL8) and necroptosis factors (RIPK1, RIPK3, MLKL) mRNA expression., Results: Pre-treatment with UA attenuated CSE-induced oxidative stress, inflammatory and necroptosis gene expression and restored mitochondrial structure and function. UA also prevented CSE-evoked increases in DRP1, MFF and SQSTM1/p62 protein expression and increased LC3B-II/I ratio. Conversely, pre-treatment with Ld aggravated CSE-induced cellular and mitochondrial responses., Conclusion: In conclusion, mitophagy mediates CSE-induced damage and inflammation of lung epithelial cells and may represent a therapeutic target in CS-driven diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The internalization of Aspergillus fumigatus into alveolar epithelial cells (AECs) is tightly controlled by host cellular actin dynamics, which require close modulation of the ADF (actin depolymerizing factor)/cofilin family. However, the role of cofilin in A. fumigatus internalization into AECs remains unclear. Results: Here, we demonstrated that germinated A. fumigatus conidia were able to induce phosphorylation of cofilin in A549 cells during the early stage of internalization. The modulation of cofilin activity by overexpression, knockdown, or mutation of the cofilin gene in A549 cells decreased the efficacy of A. fumigatus internalization. Reducing the phosphorylation status of cofilin with BMS-5 (LIM kinase inhibitor) or overexpression of the slingshot phosphatases also impeded A. fumigatus internalization. Both the C. botulimun C3 transferase (a specific RhoA inhibitor) and Y27632 (a specific ROCK inhibitor) reduced the internalization of A. fumigatus and the level of phosphorylated cofilin. β-1,3-glucan (the major component of the conidial cell wall) and its host cell receptor dectin-1 did not seem to be associated with cofilin phosphorylation during A. fumigatus infection. Conclusion: These results indicated that cofilin might be involved in the modulation of A. fumigatus internalization into type II alveolar epithelial cells through the RhoA-ROCK-LIM kinase pathway. [ABSTRACT FROM AUTHOR]

Syndecan-4 (SDC4) is a transmembrane heparin sulfate proteoglycan that regulates inflammatory responses, cell motility, cell adhesion and intracellular signaling. In this study, we found that overexpression of SDC4 promoted the infection efficiency of Mycobacterium tuberculosis (Mtb), whereas knockdown of SDC4 reduced the infection efficiency, suggesting that SDC4 assisted Mtb infection of epithelial cells. We also observed that Mtb infection affected the F-actin/G-actin ratio, which was also correlated with SDC4 expression levels. Analysis of the Cdc42, N-WASP, and Arp2/3 signaling pathways during Mtb infection revealed that knockdown of Cdc42 and N-WASP or the addition of ZCL278, Wiskostatin or CK636 (blockers of Cdc42, N-WASP, and Arp2/3, respectively) significantly exacerbated Mtb infection in lung epithelial cells. Taken together, our data indicate that SDC4 assists Mtb infection of epithelial cells by regulating the Cdc42, N-WASP, and Arp2/3 signaling pathways, which regulate the polymerization of the actin cytoskeleton. [ABSTRACT FROM AUTHOR]

Oxidative stress in the lung epithelial A549 cells and macrophages J774A.1 due to contact with commercially important nanomaterials [i.e., nano-silver (nAg), nano-alumina (nAlO), single-wall carbon nanotubes (CNT), and nano-titanium oxide anatase (nTiO)] was evaluated. Nanomaterial-induced intracellular oxidative stress was analyzed by both HDCFDA fluorescein probe and GSH depletion, extracellular oxidative stress was assessed by HHFF fluorescein probes, and the secretion of chemokine IL-8 by A549 cells due to elevation of cellular oxidative stress was also monitored, in order to provide a comprehensive in vitro study on nanomaterial-induced oxidative stress in lung. In addition, results from this study were also compared with an acellular 'ferric reducing ability of serum' (FRAS) assay and a prokaryotic cell-based assay in evaluating oxidative damage caused by the same set of nanomaterials, for comparison purposes. In general, it was found that nanomaterial-induced oxidative stress is highly cell-type dependent. In A549 lung epithelial cells, nAg appeared to induce highest level of oxidative stress and cell death followed by CNT, nTiO, and nAlO. Different biological oxidative damage (BOD) assays' (i.e., HDCFA, GSH, and IL-8 release) results generally agreed with each other, and the same trends of nanomaterial-induced BOD were also observed in acellular FRAS and prokaryotic E. coli K12-based assay. In macrophage J774A.1 cells, nAlO and nTiO appeared to induce highest levels of oxidative stress. These results suggest that epithelial and macrophage cell models may provide complimentary information when conducting cell-based assays to evaluate nanomaterial-induced oxidative damage in lung. [ABSTRACT FROM AUTHOR]

The mechanisms of poultry particulate matter (PM)-induced agricultural respiratory disorders are not thoroughly understood. Hence, it is hypothesized in this article that poultry PM induces the release of interleukin-8 (IL-8) by lung epithelial cells that is regulated upstream by the concerted action of cytosolic phospholipase A (cPLA) and extracellular signal-regulated kinase (ERK). To test this hypothesis, the widely used cultured human lung epithelial cells (A549) were chosen as the model system. Poultry PM caused a significant activation of PLA in A549 cells, which was attenuated by AACOCF (cPLA inhibitor) and PD98059 (ERK-1/2 upstream inhibitor). Poultry PM induced upstream ERK-1/2 phosphorylation and downstream cPLA serine phosphorylation, in a concerted fashion, in cells with enhanced association of ERK-1/2 and cPLA. The poultry PM-induced cPLA serine phosphorylation and IL-8 release were attenuated by AACOCF, PD98059, and by transfection with dominant-negative ERK-1/2 DNA in cells. The poultry PM-induced IL-8 release by the bone marrow-derived macrophages of cPLA knockout mice was significantly lower. For the first time, this study demonstrated that the poultry PM-induced IL-8 secretion by human lung epithelial cells was regulated by cPLA activation through ERK-mediated serine phosphorylation, suggesting a mechanism of airway inflammation among poultry farm workers. [ABSTRACT FROM AUTHOR]

Abstract: Lysophosphatidic acid (LPA), a simple bioactive phospholipid, is present in biological fluids such as plasma and bronchoalveolar lavage (BAL). It appears to have both pro- and anti-inflammatory roles in inflammatory lung diseases. Exogenous LPA promotes inflammatory responses by regulating the expression of chemokines, cytokines, and cytokine receptors in lung epithelial cells. In addition to the modulation of inflammatory responses, LPA regulates cytoskeleton rearrangement and confers protection against lung injury by enhancing lung epithelial cell barrier integrity and remodeling. The biological effects of LPA are mediated through its cell surface G-protein coupled LPA1–7 receptors. The roles of LPA receptors in lung fibrosis, asthma, and acute lung injury have been investigated using genetically engineered LPA receptor deficient mice and there appears to be a definitive role for endogenous LPA and its receptors in the pathogenesis of pulmonary inflammatory diseases. This review summarizes recent reports on the role of LPA and its receptors in the regulation of lung epithelial inflammatory responses and remodeling. This article is part of a Special Issue entitled: Advances in Lysophospholipid Research. [Copyright &y& Elsevier]